Certain thieno(2,3-c)pyridines

ABSTRACT

THIENOPYRIDINE DERIVATIVES OF THE FORMULA   2-NH2,3-X,6-R-4,5,6,7-TETRAHYDROTHIENO(2,3-C)PYRIDINE   WHEREIN R IS H, ACETYL, ALLYL, 2-PROPYNYL, 3-CHLORO-2-HYDROXYPROPYL, CARBOXYMETHYL, ALKYL OR 1 TO 8 CARBON ATOMS, ALKOXYCARBONYL WHEREIN THE ALKOXY MOIETY CONTAINS FROM 1 TO 4 CARBON ATOMS, HYDROXYALKYL WHEREIN THE ALKYL MOIETY CONTAINS FROM 1 TO 4 CARBON ATOMS, ALKOXYCARBONYLALKYL WHEREIN THE ALKOXY AND ALKYL MOIETIES EACH INDEPENDENTLY CONTAINS FROM 1 TO 4 CARBON ATOMS, PHENETHYL, BENZYL, MONO-, DI OR TRI-SUBSTITUTED BENZYL OR BENZOYL IN WHICH THE SUBSTITUENTS ARE CL, METHYL OR METHOXY, AND X IS CYANO, CARBAMOYL OR ALKOXYCARBONYL WHEREING THE ALKOXY MOIETY CONTAINS FROM 1 TO 4 CARBON ATOMS, ARE ANALGESIC AND ANTI-INFLAMMATORY AGENTS.

United States Patent 3,563,997 CERTAIN THIENO(2,3-c)PYRIDINES MichioNakanishi and Tetsuya Tahara, Nakatsu, Oita,

Hiroshi Imamura, Ichikawa, Chiba, and Yutaka Maruyama, Tokyo, Japan,assignors to Yoshitomi Pharmaceutical Industries, Ltd., Higashiku,Osaka, Japan No Drawing. Filed Nov. 29, 1968, Ser. No. 780,218 Claimspriority, application Japan, Dec. 4, 1967,

. 42/78,078 Int. Cl. C07d 31/50 US. Cl. 260-2943 14 Claims ABSTRACT OFTHE DISCLOSURE Thienopyridine derivatives of the formula wherein R is H,acetyl, allyl, 2-propynyl, 3-chloro-2-hy droxypropyl, carboxymethyl,alkyl of 1 to 8 carbon atoms, alkoxycarbonyl wherein the alkoxy moietycontains from 1 to 4 carbon atoms, hydroxyalkyl wherein the alkyl moietycontains from 1 to 4 carbon atoms, alkoxycarbonylalkyl wherein thealkoxy and alkyl moieties each independently contains from 1 to 4 carbonatoms, phenethyl, benzyl, mono-, dior tri-substituted benzyl or benzoylin which the substituents are Cl, methyl or methoxy, and X is cyano,carbamoyl or alkoxycarbonyl wherein the alkoxy moiety contains from 1 to4 carbon atoms, are analgesic and anti-inflammatory agents.

This invention relates to novel and therapeutically valuablethienopyridine .derivatives.

The novel thienopyridine derivatives of the invention are of theformula:

wherein R is H, acetyl, allyl, 2-propynyl, 3-chloro-2-hydroxypropyl,carboxymethyl, alkyl of 1 to 8 carbon atoms such as methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, hexyl,octyl, alkoxycarbonyl (alkoxy being of 1 to 4 carbon atoms) such asmethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, sec-butoxycarbonyl, t-butoxycarbonyl, hydroxyalkyl(alkyl being of 1 to 4 carbon atoms) such as hydroxymethyl,hydroxyethyl, hydroxypropyl, hydroxybutyl, alkyocarbonylalkyl (alkoxyand alkyl each being of l to 4 carbon atoms) such asmethoxycarbonylbutyl, butoxycarbonylmethyl, ethoxycarbonylpropyl,propoxycarbonylethyl, phenethyl, benzyl or mono-, dior tri-substitutedbenzyl or benzoyl in which the substituents are each selected from thegroup consisting of Cl, methyl and methoxy, and X is cyano, carbamoyl oralkoxycarbonyl (alkoxy being of 1 to 4 carbon atoms) such asmethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, iso-propoxycarbonyl,butoxycarbonyl, iso-butoxycarbonyl, sec-butoxycarbonyl,t-butoxycarbonyl.

3,563,997 Patented Feb. 16, 1971 The compounds of Formula I are producedby reacting a compound of the formula with a compound of the formulaX-CH -ON (III) (Y is secondary amine residue) with a compound of FormulaIII and sulfur, or by first reacting a compound of Formula II with acompound of Formula III and then reacting the compound (V) thus obwithsulfur in the presence of a secondary amine.

Moreover, the compounds of Formula I when R is other than hydrogen areproduced by reacting a compound of the formula zrnan with a compound ofthe formula R Z (VII) wherein R is equivalent to 'R excluding hydrogen,and Z is halogen (e.g., Cl, Br or I).

The compound of Formula II may preferably be used in the form of saltsuch as hydrochloride, especially when R is H.

These reactions are carried out in an inert solvent such as methanol,ethanol, benzene and toluene, at room temperature or at an elevatedtemperature, optionally in the presence of a dehydrating agent such asp-toluenesulfonic acid, or in the presence of a deacidifying agent suchas sodium carbonate, potassium carbonate and pyridine.

Thus-produced thienopyridine derivatives represented by Formula I canform acid addition salts with various inorganic or organic acids such ashydrochloric, hydrobromic, sulfuric, nitric, oxalic, maleic, fumaric,tartaric and malonic acids and the like.

Thienopyrimidine derivatives of Formula I as well as theirpharmaceutically acceptable acid addition salts are useful as analgesicand anti-inflammatory agents. For example, compounds of Formula I listedbelow have the following pharmacological properties.

(1) Inhibition of carrageenin edema (Donryu rat, male; to 200 grams)observed according to the method described by Charles A. Winter et al.in Proceedings of the Society for Experimental Biology and Medicine, NewYork, vol. 111, pp. 544-547 (1962).

TABLE 1 Dose (mg/kg.) Inhibition EDfiU per 05 (percent) s/ Compound:

250 51 50 as F 100 41 105 250 56 50 s Phenylbutazone 100 380 250 44 100as Aminopyrine 250 49} 210 Remarks: A:Z-amino-6-benzyl-3-methoxycarbonyl-4,5,6,7-

tetrahydro-thieno(2,3-c)pyridine B:2-amino-6-ethoxycarbonyl-3-methoxycarbonyl- 4,5 ,6,7-tetrahydro-thieno(2,3 -c) pyridine C: 2-amino-6-benzyl-3-ethoxycarbonyl-4,5,6,7-

tetrahydro-thieno(2,3-c)pyridine D:2-amino-6-benzyl-3-ethoxycarbonyl-4,5,6,7-

tetrahydro-thieno(2,3-c)pyridine hydrochloride E:6-acetyl-2-arnino-3-ethoxycarbonyl-4,5,6,7-

tetrahydro-thieno(2,3-c)pyridine F:2-amino-6-benzyl-3-cyano-4,5,6,7-tetrahydrothieno(2,3-c)pyridine G:2-amin0-6-butyl-3-ethoxycarbonyl-4,5,6,7-tetrahydro-thieno(2,3-c)pyridine hydrochloride (2) Effect on the reaction-threshold to thecarrageenin inflamed rats paw (Donryu rat, male; 120 to 180 grams) 150minutes after oral administration of the compound (I) observed accordingto the method described in Archives Internationales de Pharmacodynamieet de Therapie vol. 111, 409-419 (1957).

TABLE 2 Reaction-threshold (mmHg) N on- Dose Infiamed inflamed [Tso' e/a) p p a/ Compound:

100 203. 5 216. 4 .2 a 5 2 C 100 174. 0 165. e 47 250 225. s 179. 6 .2a: 122- .4 D 50 204 s 143. 2 5

100 21. 9. 4 152. s 5% 1 3i is g F 100 141: 2 142: 0 72 250 194. s 149.e 58 s 8 9. 2 G 100 167. e 143. 6 68 250 208.5 222.0 .2 a: 5.6Phenylbutazone 100 In 2 4 250 250 107. e 134. 4 58 11198.0 141. 6 .s145. e Meienamic acid L 100 148' 8 6 94 'IT is the dose required tocause increase of the reaction-threshold by 50 mm. Hg.

"Compou d de gnation is the me as n T b e Acute toxicity (LD of2-amino-6-benzyl-3-ethoxycarbonyl-4,5,6,7-tetrahydro-thieno(2,3-c)pyridinehydrochloride is as follows:

The compounds (I) of the invention and pharmaceutically acceptable acidaddition salts thereof can be administered safely per se as analgesicsand anti-inflammatory agents or in the form of a pharmaceuticalcomposition in admixture with a suitable and conventional carrier oradjuvant, administrable orally or by way of injection, without causingharm to the host.

The pharmaceutical composition can take the form of tablets, granules,powders, capsules, etc. for oral administration; or of injectablesolution for subcataneous or intramuscular administration; or of cream,ointment, suppository, etc. for topical administration.

Among these preparations, forms of tablets, granules, powders, andcapsules are especially preferable.

The choice of carrier is determined by the preferred form ofadministration, the solubility of the compounds and standardpharmaceutical practice. The following are examples of formulations whena compound of the present invention is administered for thepharmaceutical purposes.

(A) 25 mg. capsule Compound I 25 Lactose Starch 34 Magnesium stearate 1(B) 25 mg. tablet Compound I 25 Microcrystalline cellulose 1O Lactose 64Starch 20 Magnesium stearate 1 (C) 1% cream Compound I 10 White vaseline250 Stearyl alcohol 250 Glycerol 120 Sodium lauryl sulfate 10 Methylp-hydroxybenzoate 0.25

Propyl-p-hydroxybenzoate 0.25 Water, a sufficient quantity to make 1kilogram.

(D) 1% ointment Compound I 10 White vaseline 890 Solid paraifin 30Beeswax 20 Cetostearyl alcohol (B.P. 1963, p. 148) 50 (E) mg.suppository Compound I mg 100 Witespol E75 g 1.4

Witespol H15 g 0.5

1 Product of Chemisc'he Werke Witten, mixture of the triglycerides ofnatural saturated vegetable fatty acids of the chain length of C Ccontaining a quantity of partial glycerides, registered trade names.

Usual daily dose of the compound (I) or salt thereof, lies in the rangeof about 25 to about 300 milligrams more practically about 100 to about200 milligrams per human adult. Thus, in case of capsules eachcontaining 25 milligrams of compound (I) or salt thereof, one to twelvecapsules per day are administered.

These compositions are especially useful for the treatment of pain,redness and swelling due to post-operative pain, urological disease ordental disease.

In the following illustrative examples, g. stands for gram(s) and ml.for milliliter(s).

EXAMPLE 1 A solution of 18.9 g. of 1-benzyl-4-piperidone, 10.0 g. ofmethyl cyanoacetate, 3.4 g. of powdery sulfur and 10.0 g. of morpholinein 60 ml. of methanol is heated moderately under reflux for about 20minutes to dissolve the powdery sulfur. The mixture is heated underreflux for one further hour to complete the reaction. On standing atroom temperature, the mixture yields a precipitate. The precipitate iscollected by filtration, washed well with methanol, and recrystallizedfrom methanol to give 27.3 g. (91% yield) of2-amino-6-benzyl-3-methoxycarbonyl- 4,5,6,7-tetrahydro-thieno(2,3-c)-pyridine as almost colorless needles melting at 124 to 126 C.

EXAMPLE 2 A solution of 22.3 g. of 1-p-chlorobenzyl-4-piperidone, 11.3g. of ethyl cyanoacetate, 3.3 g. of powdery sulfur and ml. ofdiethylamine in 70 ml. of ethanol is heated at 40 C. for 30 minutes andfurther heated under reflux for 30 minutes. On standing at roomtemperature, the mixture yields a precipitate. The latter is collectedby filtration and recrystallized from ethanol to give 30.2 g. (87%) of2- amino6-p-chlorobenzyl-3-ethoxycarbonyl-4,5,6,7-tetrahydro-thieno-(2,3-c)pyridineas pale yellow needles melting at 133 to 134 C.

A solution of 1.0 g. of the product in 2 ml. of ethanol is added to ml.of a 10% hydrochloric acid solution. The precipitate crystals arecollected by filtration and recrystallized from a 70% aqueous ethanol togive 095 g. of the hydrochloride as colorless needles melting at 225 to228 C. with decomposition.

EXAMPLE 3 A solution of 18.9 g. of 1-benzyl-4-piperidone, 6.6 g. ofmalononitrile, 3.4 g. of sulfur and 9.0 g. of morpholine in 50 ml. ofethanol is heated under reflux for 2 hours. After cooling, theprecipitated crystals are collected by filtration and recrystallizedfrom ethanol to give 24.0 g. (93%) of 2amino-6-benzyl-3-cyano-4,5,6,7-tetrahydrothieno(2,3-c)pyridine as paleyellow prismatic crystals melting at 149 to 152 C.

Its yellow prismatic hydrochloride melts at 238 C. to 240 C. withdecomposition.

EXAMPLE 4 A mixture of 22.6 g. of 1-methyl-4-piperidone, 11.3 g. ofethyl cyanoacetate, 1.6 g. of ammonium acetate, 2.4 g. of glacial aceticacid and 70 ml. of benzene is heated under reflux for 3 hours in a flaskconnected with a condenser provided with a water-removing adapter, toremove 3.8 ml. of Water. After cooling, the mixture is washed with 100ml. of a cold 10% aqueous potassium carbonate solution, and dried oversodium sulfate. The crude ethyl(1-rnethyl-4-piperidine)cyanoacetateremaining after the benzene removal in vacuo is dissolved in 100 ml. ofethanol. To the ethanolic solution are added, 6.6 g. of sulfur and 19.0g. of morpholine and the whole is heated under reflux for 1.5 hours.After the ethanol is distilled ofi in vacuo, 20% aqueous ethanol isadded to the residue. The precipitated crystals are collected byfiltration and recrystallized from 50% aqueous ethanol to give 40.1 g.(80.2%) of 2-amino-3-ethoxycarbonyl-6-methyl-4,5,6,7-tetrahydro-thieno(2,3-c)-pyridine containing /2 moleculeof water of crystallization as pale yellow prismatic crystals melting at103 to 105 C.

Its hydrochloride in the form of colorless needles, recrystallized from80% aqueous ethanol, melts at 239 to 241 C. with decomposition.

EXAMPLE 5 A solution of 9.4 g. of l-benzyl-4-piperidone, 7.0 g. of butylcyanoacetate, 1.7 g. of sulfur and 4.5 g. of morpholine in 30 ml. ofethanol is heated under reflux for 2 hours. The mixture is allowed tostand overnight in an icebox, whereby crystals precipitate out. They arecollected by filtration, washed with cold ethanol, and recrystallizedfrom ethanol to give 15.2 g. (88.5%) of 2-amino-6-benzyl-3-butoxycarbonyl 4,5,6,7 tetrahydrothieno (2,3-c)pyridine as colorless prismatic crystals melting at 60 to 64 C. withdecomposition.

Its hydrochloride in the form of pale yellow needles melts at 214 to 216C.

EXAMPLE 6 A mixture of 14.1 g. of l-acetyl-piperidone, 9.0 g. ofmorpholine, 0.2 g. of p-toluenesulfonic acid and 50 ml. of benzene isheated under reflux for 8 hours in a flask connected with a condenserprovided with a water-removing adapter, to remove 1.8 ml. of water.After filtering, the benzene is distilled oif in vacuo, and theremaining brown viscous crude1-acetyl-4-morpholino-l,2,5,6-tetrahydropyridine is dissolved in 50 ml.of ethanol, and 11.0 g. of ethyl cyanoacetate and 3.2 g. of sulfur areadded. The whole is stirred at room temperature for 20 minutes and thenheated under reflux for 30 minutes to complete the reaction. Cooling toroom temperature affords precipitates, which are collected by filtrationand recrystallized from ethanol to give 20.2 g. (76%) of 6-acetyl-2-amino 3 ethoxycarbonyl 4,5,6,7 tetrahydrothieno- (2,3-c)pyridine ascolorless needles melting at 148 to 151 C.

EXAMPLE 7 A mixture of 8.5 g. of 4-piperidone, 11.3 g. of ethylcyanoacetate, 3.2 g. of powdery sulfur, 30 ml. of ethanol and 9 ml. ofmorpholine is heated with stirring at 40 C. for 30 minutes and then at60 C. for 20 minutes, to dissolve the sulfur. After cooling to roomtemperature, crystals precipitated are collected by filtration andrecrystallized from ethanol to give 11.6 g. (51.3%) of Z-amino-3-ethoxycarbonyl 4,5,6,7 tetrahydro-thieno(2,3-c)pyridine as colorlessneedles melting at 119 to 120 C.

Its hydrochloride melts at 249 to 251 C. with decomposition.

EXAMPLE 8 A mixture of 13.6 g. of 4-piperidone hydrochloride, 11.3 g. ofethyl cyanoacetate, 3.3 g. of sulfur, 100 ml. of ethanol and 9 ml. ofmorpholine is heated with stirring at 60 C. for 20 minutes, the sulfurdissolving and needles beginning to precipitate. The mixture is heatedfor further 10 minutes and then cooled to room temperature. Theprecipitated crystals are collected by filtration and recrystallizedfrom 70% aqueous ethanol to give 20.2 g. (76.5%) of2-amino-3-ethoxycarbonyl-4,5,6,7-tetrahydrothieno(2,3-c)pyridinehydrochloride as colorless needles melting at 249 to 251 C. withdecomposition.

EXAMPLE 9 A mixture of 13.6 g. of 4-piperidone hydrochloride, 14.1 g. ofbutyl cyanoacetate, 3.2 g. of sulfur, 9 ml. of morpholine and ml. ofethanol is heated with stirring at 40 to 50 C. for about 30 minutes, todissolve the sulfur. On standing at room temperature, crystalsprecipitate. They are collected by filtration and recrystallized from90% aqueous ethanol to give 21.0 g. (72%) of 2- amino 3 -'butoxycarbonyl4,5,6,7 tetrahydro-thieno- (2,3-c)pyridine hydrochloride as colorlessneedles melting at 223 to 225 C. with decomposition.

Its free base in the form of colorless needles melts at 90 to 93 C.

EXAMPLE A mixture of 13.6 g. of 4-piperidone hydrochloride, 6.6 g. ofmalononitrile, 3.2 g. of sulfur, 9 ml. of morpholine and 150 ml. ofethanol is heated with stirring at 50 C. for minutes, the sulfurdissolving and crystals beginning to precipitate. On standing at roomtemperature, crystals precipitate. They are collected by filtration andrecrystallized from aqueous ethanol to give 14.5 g. (63%) of 2amino-3-cyano-4,5,6,7-tetrahydro-thieno- (2,3-c)pyridine hydrochlorideas pale yellow prismatic crystals melting at 260 to 263 C. withdecomposition EXAMPLE 11 A mixture of 22.6 g. of2-amino-3-ethoxycarbonyl- 4,5,6,7 tetrahydro-thieno(2,3-c)pyridine, 9.5g. of 3- chloropropanol, 12.0 g. of potassium carbonate and 100 ml. ofethanol is heated under reflux for 24 hours. After cooling, the reactionmixture is filtered to remove insoluble matter, and 20 ml. of 29%ethanolic hydrochloric acid is added to the filtrate. Crystalsprecipitated are collected by filtration by means of suction, washedwith ethanol, and recrystallized from ethanol to give 22.8 g. of2-arnino-3-ethoxycarbonyl-6- 3-hydroxypropyl) 4,5,6,7-tetrahydro-thieno(2,3-c pyridine hydrochloride as colorless needlesmelting at 230 to 231 C. with decomposition.

EXAMPLE 12 Monochloroacetic acid (4.8 g.) is added to a solution of 2.0g. of sodium hydroxide in ml. of 95% ethanol, and the whole is wellstirred to form a suspension of sodium monochloroacetate. To thesuspension are added 10.5 g. of2-amino-3-ethoxycarbonyl-4,5,6,7-tetrahydrothieno(2,3-c)pyridine and 7g. of potassium carbonate. The mixture is heated under reflux for 6hours. After cooling, the reaction mixture is filtered to removeinsoluble matter, and the filtrate is adjusted to pH 7 with 200 ml. of10% hydrochloric acid. The resulting precipitates are collected byfiltration by means of suction, and recrystallized fromdimethylformamide to give 8.1 g. of Z-amino- 6 carboxymethyl 3ethoxycarbonyl-4,5,6,7-tetrahydrothieno(2,3-c)pyridine as colorlesspowder melting at 250 to 254 C. with decomposition.

In the same manner as in the above examples, the following thieno(2,3-c)pyridine derivatives are also produced:

(13) 2-amino-6-ethoxycarbonyl 3 methoxycarbonyl-4,5,6,7-tetrahydro-thieno(2,3-c)pyridine as colorless prismatic crystalsmelting at 147 to C.;

(14) 2-amino 6 cyclohexyl-3-ethoxycarbonyl-4,5,6,7-tetrahydro-thieno(2,3-c)pyridine as pale yellow needles melting at 87 to90 C., and its hydrochloride as colorless needles melting at 232 to 235C. with decomposition;

(15) 2 amino 3,6diethoxycarbonyl-4,5,6,7-tetrahydro-thieno(2,3-c)pyridine as colorlessprismatic crystals melting at 142 to 144 C.;

(16) 2-amino 6butyl-3-ethoxycarbonyl-4,5,6,7-tetrahydro-thieno(2,3-c)pyridinehydrochloride as colorless needles melting at 182 to 186 C. withdecomposition;

(l7) 2amino-6-benzyl-3-eth0xycarbonyl-4,5,6,7-tetrahydro-thieno(2,3-c)pyridineas colorless needles melting at 112 to 113 C., and its hydrochloride ascolorless needles melting at 234 to 235 C. with decomposition;

(18) 2-amino-6-p-chlorobenzoyl 3 ethoxycarbonyl-4,5,6,7tetrahydro-thieno(2,3-c) pyridine as colorless prismatic crystalsmelting at 215 to 219 C.;

(19) 2-amino-3-ethoxycarbonyl 6 phenethyl-4,5,6,7tetrahydro-thieno(2,3-c)pyridine hydrochloride as color less needlesmelting at 214 to 215 C. with decomposition;

(20) 6-allyl-2-amino 3ethoxycarbonyl-4,5,6,7-tetrahydro-thieno(2,3-c)pyridine melting at 71 to74 C., and

8 its hydrochloride melting at 234 to 236 C. with decomposition;

(21) Z-amino 3 ethoxycarbonyl-6-(2-propynyl)-4,5,6,7-tetrahydro-thieno(2,3-c)pyridine melting at 70 to 73 C., and itshydrochloride melting at 237 C. with decomposition;

(22) 2-amino 3 ethoxycarbonyl-6-m-methylbenzyl-4,5,6,7-tetrahydro-thieno(2,3-c)pyridine hydrochloride as pale yellowneedles melting at 228 to 231 C. with decomposition;

(23) 2 amino 3 ethoxycarbonyl 6 (2-methoxy-5- methylbenzyl) 4,5,6,7tetrahydro-thieno(2,3-c) pyridine hydrochloride as colorless needlesmelting at 218 to 220 C. with decomposition;

(24) Z-amino 3ethoxycarbonyl-6-(3,4,5-trimethoxybenzyl)-4,5,6,7-tetrahydro-thieno(2,3-c)pyridineas colorless needles melting at 141 C., and its hydrochloride ascolorless needles melting at 228 to 230 C. with decomposition;

(25) 2-amino-3-ethoxycarbonyl 6 octyl-4,5,6,7-tetrahydro-thieno(2,3-c)pyridine hydrochloride as pale yellow needles melting at to 193 C.;

(26) 2-amino 3 carbamoyl-4,5,6,7-tetrahydro-thieno- (2,3-c)pyridinemelting at 202 to 203 C. with decomposition;

(27) 2-amino-3-carbamoyl 6methyl-4,5,6,7-tetrahydro-thieno(2,3-c)pyridine melting at 186 to 189 C.with decomposition;

(28) 2-amino-6-benzyl 3 carbamoyl-4,5,6,7-tetrahydro-thieno(2,3-c)pyridine hydrochloride containing /2 molecule of water ofcrystallization melting at 222 to 225 C. with decomposition;

(29) 2-amino-3-carbamoyl 6 ethoxycarbonyl-4,5,6,7-tetrahydro-thieno(2,3-c)pyridine melting at 179 to 182 C. withdecomposition;

(30) Z-amino 3 carbamoyl-6-p-chlorobenzoyl-4,5,6,7-tetrahydro-thieno(2,3-c)pyridine melting at 208 to 211 C. withdecomposition;

(31) Z-amino 3 ethoxycarbonyl-6-(2-hydroxybutyl)-4,5,6,7-tetrahydro-thieno(2,3-c)pyridine melting at 104 to 106 C.;

(32) 2 amino 6 (3 chloro 2 hydroxypropyl)-3- ethoxycarbonyl4,5,6,7-tetrahydro-thieno(2,3-c)pyridine melting at 119 to l2 C.;

(33) 2-amino 3 ethoxycarbonyl-6-(2-ethoxycarbor1-ylethyl)-4,5,6,7-tetrahydro-thieno(2,3 c) pyridine hydrochloride meltingat 176 to 181 C. with decomposition;

(34) 6-acetyl-2-arnino 3 carbamoyl4,5,6,7-tetrahydrothieno(2,3-c)pyridine melting at 248 to 251 C. withdecomposition;

(35) 2-amino-6-butyl 3 carbamoyl 4,5,6,7-tetrahydro-thieno(2,3-c)pyridine hydrochloride containing /3 molecule of water ofcrystallization melting at 167 to 168 with decomposition;

(36) 2 amino 3 carbamoyl-6-(2-propynyl)-4,5,6,7-tetrahydro-thieno(2,3-c)pyridine hydrochloride melting at 219 to 220 C.with decomposition;

(37) 2-amino 6 allyl 3carbamoyl-4,5,6,7-tetrahydro-thieno(2,3-c)pyridine hydrochloride meltingat 216 to 219 C. with decomposition.

What is claimed is:

1. A compound of the formula wherein R is a member selected from thegroup consisting of H, acetyl, allyl, 2-propynyl,3-chloro-2-hydroxypropyl, alkyl of 1 to 8 carbon atoms, hydroxyalkylwherein the alkyl moiety contains from 1 to 4 carbon atoms, phenethyl,benzyl, mono-, dior tri-substituted benzyl and benzoyl in which thesubstituents are selected from the group consisting of Cl, methyl andmethoxy, and

X is alkoxycarbonyl wherein the alkoxy moiety contains from 1 to 4carbon atoms.

2. A pharmaceutically acceptable acid addition salt of a compound as inclaim 1.

3. A compound as claimed in claim 2, wherein the pharmaceuticallyacceptable acid addition salt is the hydrochloride.

4. A compound as in claim 1, said compound being 2 amino 6benzyl-3-methoxycarbonyl-4,5,6,7-tetrahydro-thieno(2,3-c)pyridine. v

5. A compound as in claim 1, said compound being 2 amino -6 benzyl 3ethoxycarbonyl 4,5,-6,7 tetrahydrothieno(2,3-c)pyridine.

6. A compound as in claim 1, said compound being 6 acetyl 2 amino 3ethoxycarbonyl 4,5,6,7 tetrahydrothieno(2,3-c)pyridine.

. 7. A compound as in claim 1, said compound being 2 amino 6 butyl 3ethoxycarbonyl 4,5,6,7 tetrahydrothieno(2,3-c)pyridine.

8. A compound as in claim 1, said compound being 2 amino 3ethoxycarbonyl 6 phenethyl 4,5,6,7- tetrahydrothieno(2,3-c)pyridine.

9. A compound as in claim 1, said compound being 2 amino 3ethoxycarbonyl 6 methyl 4,5,6,7 tetrahydrothieno(2,3-c)pyridine.

10. A compound as in claim 1, said compound being 2 amino 6 pchlorobenzyl 3 ethoxycarbonyl- 4,5,6,7-tetrahydrothieno(2,3-c)pyridine.

11. A compound as in claim 1, said compound being 6 allyl 2 amino 3ethoxycarbonyl 4,5,6,7 tetrahydrothieno(2,3-c)pyridine.

12. A compound as in claim 1, said compound being 2 amino 6 benzyl 3butoxycarbonyl 4,5,6,7 tetrahydrothieno(2,3-c)pyridine.

13. A method for producing thienopyridine derivatives of the formulawherein R and X are as defined in claim 1, which comprises reacting acompound of the formula with a compound of the formula XCH CN and sulfurin the presence of a secondary amine.

14. A process which comprises reacting a compound of the formula whereinX is as defined in claim 1 to produce a compound of the formula andsubsequently reacting said compound with a compound of the formula R-Zwherein Z represents halogen and R a member selected from the groupconsisting of acetyl, allyl, Z-propynyl, 3-chloro-2-hydroxypropyl,carboxyrnethyl, alkyl of 1 to 8 carbon atoms, alkoxycarbonyl wherein thealkoxy moiety contains from 1 to 4 carbon atoms, hydroxyalkyl whereinthe alkyl moiety contains from 1 to 4 carbon atoms, alkoxycarbonylalkylwherein the alkoxy and alkyl moieties each independently contain from 1to 4 carbon atoms, phenethyl, benzyl, mono-, dior tri-substituted benzyland benzoyl in which the substituents are selected from the groupconsisting of Cl, methyl and methoxy.

References Cited ALAN L. ROTMAN, Primary Examiner US. Cl. X.R.

